HIV-1 enters the brain early after infection and is neuropathogenic in some individuals despite generally effective antiretroviral therapy. Macrophages and microglial cells are the major target for productive infection by HIV-1 in the brain but the cellular basis for disease development is not fully defined. In the previous funding cycle of this grant, we discovered a new pattern of macrophage activation by HIV-1. We found that macrophages mount an NFkB-driven innate immune response to HIV-1 gp120 that is strain specific but not governed by coreceptor usage or virus replication The group of inflammatory genes expressed during acute responses to certain R5 and X4 HIV-1 strains is distinct from the genes expressed during the chronic response at the peak of productive infection by R5 HIV-1. In this application we propose to determine the relative contributions of the acute innate immune response and the chronic response to HIV-1 of macrophages and microglial cells to neuropathogenesis during infection in the brain. We will also investigate whether gp120 activates macrophages through interaction with a Toll-like receptor. The Specific Aims are 1) To define distinct programs of cellular gene expression during "acute" and "chronic" responses of monocyte-derived macrophages to HIV-1. 2) To determine the roles of gp120 and Tat in HIV-1 induction of acute or chronic responses by MDM. 3) To determine the intermediate steps in NFkB and STAT 1 activation observed in acute or chronic responses of macrophages to HIV-1. 4) To define the predominant response of monocytes and microglial cells to HIV-1. 5) To determine whether HIV-1 infected or uninfected macrophages/microglia cells express acute or chronic response proteins in the brains of infected persons suffering had or infected persons without brain disease.